Could Yellow Fever Become the Next Pandemic?

Kinshasa, Democratic Republic of the Congo--In the doorway of a one-room yellow fever ward in downtown Kinshasa, a toddler named Julia is slung over her mother’s shoulder. Moments later a nurse directs mother and child to the last vacant bed and inserts an intravenous line into the girl’s wrist. Her lemon-yellow eyes staring vacantly ahead, Julia does not flinch as the needle punctures her skin. She could be awaiting a hand massage or a manicure.

In the bed adjacent to her, 12-year-old Elohim has one knee propped up like a tent stake. His palms and the skin under his fingernails are yellow with jaundice. His gaze trails up a fluid line that coils around the bed net up to his IV bag as he watches it drain.

“Suspected case,” the 50-year-old nurse, Paul Djonga, mutters in French--jabbing his thumb over his shoulder toward the headboard where the boy is draped. “Suspected?” I ask, certain that a diagnosis could be easily confirmed with a lab test. Djonga nods. “They’re all only ‘suspected,’” he says. The necessary blood tests to verify a diagnosis have not been conducted.

The lack of confirmation will not, for the most part, make much of a difference for Julia, Elohim or any of the other patients on the ward. Health care workers give the patients fluids, oxygen and other standard treatments designed to keep them going until their own immune systems either fight off the virus or they die. But nevertheless, the missing diagnoses have troubling implications for the rest of the world. They mean the yellow fever outbreak that began creeping through Angola in December 2015 and then spread to the neighboring Democratic Republic of the Congo (DRC) earlier this year is nowhere near as well controlled as it should be at this point--eight months into the outbreak.

Indeed, yellow fever could be on the verge of exploding out of central Africa and spreading to Asia, which has never before suffered a major outbreak. The most likely route of transmission: any one of the thousands of unvaccinated Chinese expatriates who are building roads, dams and other big projects in the region. Health authorities already know of at least a dozen workers who returned to China earlier this year and turned out to be sick with yellow fever. How many more infected workers might escape official notice and quarantine, thereby allowing the mosquito-borne virus to gain a toehold in a new part of the world?

The World Health Organization is rushing to play catch-up, planning to send millions more doses of vaccine, extra supplies and even a mobile lab to test samples in distant parts of the DRC. But there are no guarantees that all the extra equipment, even if it arrives quickly, will halt the spread of yellow fever before October and the traditional start of the rainy season. A reporting trip to the DRC in July revealed just how haphazard the response has been to date.

Because there is not enough yellow fever vaccine in existence to protect the entire country, let alone the world, health officials in the DRC must be selective in their efforts to keep the virus from spreading. The idea is to stop transmission by vaccinating everyone who lives near a yellow fever patient while spraying against mosquitoes and draining the standing pools of water where the insects lay their eggs. Thus, health care workers from the country’s Ministry of Health and other groups depend on laboratory confirmation of yellow fever cases to tell them whom to vaccinate and where to spray.

Every health official I spoke to in Kinshasa on my recent visit enthusiastically told me the same thing: “We haven’t seen any cases of local transmission in months!” It was good news but incongruent with what I had witnessed in the hospital. If clinicians were not conducting confirmatory lab tests on patients, then how could anyone be sure the yellow fever threat had passed?

A visit to the National Institute of Biomedical Research (INRB), the government lab running yellow fever diagnostic tests, exposed the truth. When I asked to see the testing process, Steve Ahuka, head of the institute’s Virology Department, hesitated. No one was working on suspected yellow fever blood samples that day, he said. I asked about tomorrow. He frowned. “When is the last time you tested yellow fever samples?” I asked.

Ahuka could not recall the exact date. “June 17, maybe?”

It had been at least a month since a single yellow fever diagnostic test had been conducted in the DRC. INRB had run out of the necessary reagent, I learned; the technicians had not noticed the low stock until it was spent. WHO had fast-tracked reagents to the lab but Ahuka muttered something about “perhaps a shipment problem with DHL,” something about excessive regulation of the supplies because they had been mistaken for biological samples. So far, nothing had arrived.

The visit did not reveal a lack of new yellow fever cases; instead, it exposed a lack of official diagnoses. On July 15 WHO announced a 38 percent spike in suspected cases over just three weeks. Ahuka said he expected the reagents for lab tests to arrive by the following day, but in three separate visits to INRB over the course of eight days, I found all four yellow fever testing benches vacant.

“It’s a big problem for us when INRB doesn’t know if or where we have new cases,” says Guylain Kaya Mutenda Sheria, deputy director of the Programme Élargi de Vaccination, a branch of the Ministry of Health that oversees government-led vaccination. “In way, it’s like turning off the lights.” Sheria spoke about his frustration with the intergovernmental testing hold up after consistent pressing: “We need the lights on to see. And if the lights are broken and it’s dark, there’s no way at all to see where the problems are. When they can’t give us answers, we can’t go to the areas (to vaccinate and prevent spread). We don’t move when we’re in the dark.”

Many speculate that the lack of confirmed cases is creating an illusion of decreased urgency. Vaccination around confirmed local transmission episodes in Kinshasa and Kongo Central Province finished in May, with one small vaccine drive in mid-July. MSF has led a couple of small rounds of vector control in Kinshasa in the past month. But until diagnostic lab tests are run, there is no way of knowing whether these efforts have been effective, need to be expanded or perhaps even directed elsewhere. “This is a bad management supply issue,” says Bruce Aylward, ad interim executive director of WHO’s Outbreaks and Health Emergencies Cluster. “There may be transmission happening in the DRC that isn’t being confirmed because they ran out of reagents. It’s a manageable problem…. You should be able to solve this faster than that.”

Ill-preparedness in the fight against yellow fever, unfortunately, is not new. Thanks to vaccination campaign successes in the 1940s, yellow fever went off the world’s radar for half of a century--and efforts went lax. Now only four factories produce yellow fever vaccines globally, and one is about to close for renovations. The 80-year-old low-tech process is difficult to scale up, requiring embryos from specific pathogen-free chicken flocks and an assembly line of workers manually injecting, incubating and blending. Moreover, Aylward says a vaccine takes more than 18 months to produce, from the original seed virus through release from the regulatory agencies.

Within these parameters, Aylward says the global vaccine stockpile is meant only for rapid, targeted outbreak responses. In this outbreak, by the time the Angolan government recognized the virus, requested vaccines and organized itself to vaccinate, the outbreak had taken off and spread. In a game of catch-up, response has already depleted 20 million doses this year--nearly four times the global stockpile. During distribution, at least a million vaccines went missing in Angola and many more in the region were ineffective either because they were inadequately refrigerated or because they arrived without the necessary syringes.

Now, aid groups are scrambling. On July 28 WHO announced the deployment of a mobile laboratory from the European Union to the DRC. The lab will provide testing capacity in Kahemba in Kwango Province, which is too far from INRB to send samples for time-sensitive diagnosis.

Vaccine makers cannot wait, however, until the diagnostic crisis is resolved. Because vaccine production takes 18 months, manufacturers will need to fast-track any bulk vaccine stock that is in process of being made, and tropical countries like Brazil will have to contribute some of the stocks that they would normally keep for their own protection as well. Plans are afoot to vaccinate 15.5 million more people in both countries at a cost of $34 million with still no guarantee that chain of infection can be broken. In some cases implementers will stretch their supplies by giving each person about a fifth of a dose in the hopes that it will nonetheless adequately protect them, at least for this year. Evidence of fractional dose effectiveness, however, is limited.

At any rate, a renewed vaccination campaign cannot begin until at least late August, and experts agree it must be done before the onset of rainy season in October, when the Aedes aegypti mosquitoes that carry yellow fever will find exponentially more pooled bottle caps and old tires in which to breed. In less than two months infection rates in the region will likely skyrocket.

Outside the region, it could be sooner. In a world of increased urbanization, population density and worldwide travel the stakes of each case are enormous. Chinese investment in the region means the return of a handful of ill Chinese workers’ to A. aegypti–infested Asia could spark global eruption. Of particular concern is the dengue-endemic belt of southeastern China, where dengue season, also driven by the A. aegypti mosquito, has already begun. Given the similarities between the viruses, experts are amazed that yellow fever has never apparently ravaged Asia. Still, that does not mean it won’t. “In fact, we know that yellow fever can spread to Asia because … well, it already has,” says Jack Woodall, co-founder of the Program for Monitoring Emerging Diseases (ProMED) of the International Society for Infectious Diseases. He’s referring to the 12 unvaccinated Chinese workers who returned sick with yellow fever from Angola to China earlier this year.

There are reportedly 100,000 mostly unvaccinated Chinese construction workers and business people in Angola and an untold number in the DRC. An ill China-bound traveler from either country could trigger transmission among the 100 million people living in large Chinese cities. From there yellow fever could spread to any and all 100 countries that have endemic dengue globally.

“So, we should be very worried,” Woodall says. He also warns that health officials cannot necessarily rely on travelers’ paperwork to tell them who has been vaccinated. False yellow fever vaccination documentation has historically been less expensive to obtain than the vaccine itself.

And even though WHO has declined to deem this outbreak a “public health emergency of international concern,” or PHEIC, they, too, admit the threat of global spread is unnerving. “When you ask how afraid we are, the answer is that we’re trying to vaccinate over 30 million people this year in two large urban areas in Africa,” says Aylward, referring to the 20 million vaccines already used this year, along with the 15.5 million ahead. “That is completely unprecedented in recent history of yellow fever control measures. What we’re dealing with is a high consequence event here.”

Djonga, the nurse in Kinshasa, hears the international buzz of the Zika outbreak and says he finds its visibility ironic. Zika and yellow fever are closely related--they’re carried by the same mosquito and spread the same way. Yet, whereas Zika has harmful long-term effects on adults and fetuses, it isn’t as deadly as yellow fever.

In the ward he tends a pregnant woman in the fourth bed on the right. She tells us she’s afraid of dying, killing her unborn child and leaving her other two children behind, hungry. Her tongue is swollen and yellow, and she fumbles around with each word. Djonga shakes his head, wiping sweat from his brow. “I chose to be a nurse because I have compassion and love of people. It’s despair when I have all these patients with a disease that could have been prevented.”

Djonga wishes the authorities would kick into high gear before it’s too late--and that the world would turn their heads from the frenzy of Zika, just for a moment, to recognize its cousin, who kills.

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